This invention relates to a composition and method for inducing an immune response. In particular, the invention relates to nucleic acid expression vectors encoding immunopotentiating chemokines as well as immunogenic polypeptides. The invention also relates to methods of manufacturing various immunogenic compositions, and methods of using such compositions to treat cancer and infectious disease.
The immune system protects individuals against disease and infection by viruses, bacteria or other infectious agents. The immune system is able to recognize cells of different individuals, including different allogeneic hosts. Ideally, the immune system functions to eliminate an infectious agent from a mammalian host. Specific immune mechanisms are involved in presenting infection with foreign agents, in resolution of such infections, and in control of cancer cells. Resolution of most virus infections (as well as infection with many other intracellular agents) and elimination of cancer cells is the result of a successful cellular (e.g., Th1 helper T cell and cytotoxic T cell) immune response. The cellular immune response results from activation of certain lymphocytes known as T cells.
Many traditional vaccines expose the immune system to a foreign antigen such as an antigen of an infectious agent to elicit an antigen-specific immune response. The immune response is often predominantly humoral, in which the presence of a foreign antigen elicits the production of antibodies specific for the antigen. For example, an infectious agent antigen may elicit the production of antibodies which neutralize the infectivity of the infectious agent or toxin produced by the agent. Examples include polio and hepatitis A and B, measles, Varicella-zoster, parvovirus and rabies virus antigens. Toxic antigens produced by infectious agents include tetanus toxin, botulinum toxin, diphtheria toxin and pertussis toxin. (See Fundamental Virology, Fields et al. eds., 3rd ed., Lippincott-Raven, New York 1996; and Microbiology, Davis et al. eds., 4th ed., Lippincott, New York, 1990). This is in contrast to a cellular response, e.g. by activated T cells.
Recently, vaccination using DNA fragments has emerged as a viable method for inducing an immune response in animal hosts. DNA vaccination has enormous potential to revolutionize human health by obliterating many infectious diseases, not only in the industrialized nations but also in the Third World. There have been intense efforts to develop vaccines that induce a protective response based on induction of antibodies or cellular responses. Recent studies have shown that DNA vaccination involving the direct injection into animals of genes encoding viral proteins (subunit vaccines), rather than attenuated or killed viruses, can evoke a protective effect against challenge with whole virus from which the gene was derived [Donnelly, J. J. et al.; Annu. Rev. Immunol. 15:617-648 (1997)].
Thus, direct injection into animals of a DNA expression vector, encoding a potentially pathogenic protein, has demonstrated that a protective specific immune response, both humoral and cellular, can be elicited to that protein product. It is thought that bone-marrow-derived, antigen-presenting cells (APCs) take up the DNA plasmid and express the encoded gene product in the lymph nodesxe2x80x94the tissue in which an immune response is orchestrated. This ultimately results in the generation of specific antibodies and cytotoxic T lymphocytes.
The use of subunit vaccines suffers from at least two limitations, namely, (i) the presence of certain viral proteins, e.g., HIV gp160, can themselves have deleterious effects even in the absence of infectious virus (Mellado, M., et al.; Vaccine 15:1111-1115 (1998)) and (ii) expression vectors can only be constructed to contain a limited number of genes (10-15 kb). Thus, a DNA vaccine which presents several viral proteins for recognition by the immune response must comprise a mixture of plasmids each containing 1-3 genes, which limits the amount of each vector species that can be administered.
As a consequence, there is a need to minimize the size of sequences necessary to elicit a protective immune response. The minimization of sequence size will allow the use of small vectors, which enter cells more efficiently than larger vectors, and obviate the potentially harmful effects associated with expression of whole viral proteins.
The present invention features a novel DNA expression vector for inducing an immune response in a mammalian host that includes at least one sequence encoding an immunogenic polypeptide and at least one sequence encoding an immunopotentiating chemokine capable of boosting the host""s immune response to the immunogenic polypeptide. The chemokines of the invention are preferably selected according to the animal to be treated, e.g., murine chemokines if the animal is a mouse or human chemokines for human beings.
In another aspect of the invention, the DNA expression vector is combined with a suitable carrier to yield a pharmaceutical composition that would be effective in inducing an immune response in the host.
The invention also relates to a method of inducing an immune response in a mammalian host by administering an effective amount of the pharmaceutical composition. The immune response may be in the form of a protective challenge or a therapeutic effect.
Additionally, the invention features a method for manufacturing pharmaceutical compositions comprising the step of combining the DNA expression vector of the invention with an acceptable carrier.